Biopharmaceutical product storage system

ABSTRACT

A biopharmaceutical product storage system is disclosed. In one embodiment, the system includes a polymeric product container for storage of a biopharmaceutical product, a protective envelope for housing the container, and a cushioning layer disposed between the container and the envelope. The protective envelope and the cushioning layer include mineral fibers that protect and insulate the polymeric product container during handling, transport, and storage. Thus, the combination of the polymeric product container, the protective envelope, and the cushioning layer, the system substantially prevents leakage of the biopharmaceutical product during product handling, transport, and storage. In addition, where the biopharmaceutical product is frozen, the system substantially prevents leakage of product during freeze-storage-thaw cycles, during which temperatures range from −100° C. to 8° C.

BACKGROUND

Because of the numerous benefits offered by disposable or “single use”technology, it has become an integral part of biopharmaceuticalmanufacturing. Single use technology eliminates the need for cleaning,validation, and maintenance of multi-use storage systems. By using thistechnology, biopharmaceutical manufacturers can lower cost, saveprocessing time, and utilize processing flexibility. In addition,single-use technology often provides for efficient and space-savingstorage of biopharmaceutical products. For example, multi-use stainlesssteel cryo vessels require much more space to store than flexibleplastic bags.

Production of biopharmaceuticals is expensive. To optimize use ofproduction facilities, bulk biopharmaceutical solutions produced inmanufacturing campaigns are often stored at frozen temperatures forextended periods of time until market demand is such that the bulkproduct is thawed, further purified and formulated into the finalproduct for commercial sale. Because single use technology has severaladvantages, many biopharmaceutical manufacturers prefer to freeze liquidbiopharmaceutical products in single use containers. In some cases,these products are stored and transported at temperatures as low as−100° C. Unfortunately, single-use containers are often plasticmaterials which become particularly fragile at lower temperatures. Inaddition, the freezing and thawing techniques used by manufacturers canalso adversely affect these types of container materials.

Damage to single-use containers can also occur during handling,particularly during transport and warehousing. In one study, single-usecontainers, in the form of plastic bioprocess bags, were subject toextensive manipulation to assess container resiliency under simulatedprocessing conditions. Only bags that did not leak product after testingwere considered to survive the test. The study determined that even themost resilient bags only survived 50% of the time during testing.Kilburn et al., “Evaluating Single-Use Frozen Storage Systems,” Am.Pharmaceutical Review, Apr. 12, 2010, pp. 12-18.

Unfortunately, damage to these types of single-use containers is oftennot discovered until the product is thawed. As a result, manufacturersoften have difficulty with, among other things, production schedulingand planning, and with unnecessary costs associated with storage ofunusable product. Damage to the single-use container also likely meanscompromise of the sterility of the biopharmaceutical product andtherefore loss of valuable product. Although some manufacturers haveimplemented process improvements and procedural controls to improvehandling techniques, damage to single-use containers still occurs.

In view of the potential for damage to plastic single-use containers andthe potential for monetary loss due to product leakage, a need existsfor a biopharmaceutical product storage system using single-usetechnology that can withstand worst-case product handling without damageto the biopharmaceutical product. Such systems will benefitbiopharmaceutical manufacturers by limiting loss of expensivebiopharmaceutical product due to leakage of products from the single-usecontainer resulting from container damage during handling, transport,and storage, and particularly damage incurred during freeze-storage-thawcycles.

SUMMARY

The present embodiments are directed toward a biopharmaceutical productstorage system. In one embodiment, the system includes a polymericproduct container for storage of a biopharmaceutical product, aprotective envelope for housing the filled product container, andoptionally a cushioning layer disposed within the envelope adjacent tothe container. The protective envelope and the cushioning layer comprisematerials such as mineral fibers manufactured from rock and/or slag thatinsulate and protect the product container during storage, transport,and handling.

By combining the polymeric product container, the protective envelope,and optionally the cushioning layer, the system also substantiallyprevents leakage of biopharmaceutical product during product handling,transport, and storage. In addition, where the biopharmaceutical productis frozen, the system substantially prevents leakage of product duringfreeze-storage-thaw cycles. Typically, product temperatures duringtheses cycles range from −100° C. to 8° C.

Accordingly, a biopharmaceutical product storage system is disclosed.Advantages of the system will appear from the drawings and detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exploded view of a biopharmaceutical product storagesystem;

FIG. 2A is a front elevational view of a polymeric product containerused in the system of FIG. 1;

FIG. 2B is a cross-sectional view of the polymeric product containershown in FIG. 2A;

FIG. 3 is a front elevational view of an insulation section orcushioning layer used in the system of FIG. 1;

FIG. 4 is a cross-sectional view of the insulation section or cushioninglayer shown in FIG. 3 taken along line 4-4;

FIG. 5 is a top view of a pre-assembled protective envelope;

FIG. 6 is a front elevational view of an assembled protective envelopeused in the system of FIG. 1; and

FIG. 7 is a side view of the assembled protective envelope shown in FIG.6.

DETAILED DESCRIPTION

Turning in detail to the drawings, FIG. 1 shows an exploded view of abiopharmaceutical product storage system 10. In this configuration, thesystem 10 includes a polymeric product container 12 for storage ofbiopharmaceutical product 8, a protective envelope 14 for housing thefilled product container and, optionally, at least one cushioning layer16, which upon assembly is placed between the product container 12 andthe protective envelope 14. The protective envelope 14 and thecushioning layer 16 comprise materials such as mineral fibers 28 thatinsulate and protect the product container during storage, transport,and handling.

As used herein, a biopharmaceutical product 8 refers to anybiopharmaceutical product or product intermediary which changes, at somepoint during processing, from a liquid to a frozen state. Thetemperature of the biopharmaceutical product 8 while in the liquid statetypically is maintained from 2° C. to 8° C. The temperature of thebiopharmaceutical product 8 while in the frozen state typically rangesfrom −100° C. to 0° C. Specifically, the biopharmaceutical product maybe handled, stored, and transported at temperatures at or slightly below0, −10, −20, −30, −40, −50, −60, −70, −80, −90 or −100° C. or at atemperature falling within any combination of these temperatures as anupper and lower limit, such as at 0 to −10° C. inclusive of theendpoints. Temperatures of the biopharmaceutical product while in eitherthe liquid or frozen state may also be lower or higher than thosestated, depending on the properties and processing specifications of thebiopharmaceutical product.

The biopharmaceutical product 8 may comprise a liquid solution ofrecombinant proteins, antibodies (monoclonal or otherwise), vaccines,blood/plasma-derived products, nonrecombinant culture-derived proteins,and cultured cells. The liquid solution of recombinant protein maycomprise a solution of any recombinant protein obtained from recombinantcell culture and isolated at least partially from the cell culturemedium using affinity chromatography, ion-exchange chromatography, orthe like. As used herein, “solution” includes suspensions, dispersionsand the like of the biopharmaceutical product in a liquid vehicle.

The solution may comprise a bulk solution, which is a solution which hasbeen partially purified. As used herein, a “bulk” solution comprises apartially but not fully purified liquid solution of biopharmaceuticalproduct such as a recombinant protein. Bulk solutions are furthercharacterized by their very low product concentration. In someembodiments, the solution may be of a biopharmaceutical product such asa recombinant protein at about 0.0001 micromolar, 0.001 micromolar, 0.01micromolar, or a range between 0.0001 to 0.001 micromolar or 0.001 to0.01 micromolar. In some embodiments of the invention, the concentrationof biopharmaceutical product such as a recombinant protein can be ashigh as about 10 micromolar, 1.0 micromolar, or 0.1 micromolar, or arange between 10 to 1.0 micromolar or 1.0 to 0.1 micromolar or 0.1 to0.01 micromolar or 10 to 0.01 micromolar or 10 to 0.0001 micromolar or10 to 0.001 micromolar or 10 to 0.1 micromolar or any otherconcentration falling between any combination of these upper and lowerlimits of protein concentration.

Often during production of recombinant proteins, an elution buffer ofhigh salt content is used to elute the desired protein from a first-passpurification treatment. In the case of elution from a column, a highsalt concentration is needed to release the protein from the column.Accordingly, the bulk solution recovered from first pass purificationtreatment can comprise a solution having a high concentration ofmonovalent salts, normally sodium chloride but potentially potassiumchloride or other salts. The concentration of sodium chloride orpotassium chloride in some embodiments is at least 100 millimolar, atleast 200 millimolar, at least 300 millimolar, at least 400 millimolar,at least 500 millimolar, at least 600 millimolar, at least 700millimolar, or at least 800 millimolar. The bulk solution may alsocontain varying amounts of other salts, such as divalent salts,including calcium chloride. By “partially but not fully purified” ismeant the liquid solution has been subjected to at least onepurification step, but the liquid solution still contains sufficientresidual impurities that at least one further purification step isrequired prior to final product formulation. For example, a “bulk”solution of recombinant Factor VIII must be further purified prior tofinal formulation, which in the case of Factor VIII and other proteinsmay include lyophilization.

Recombinant proteins include, for example and without limitation,coagulation factors, virus antigens, bacterial antigens, fungalantigens, protozoal antigens, peptide hormones, chemokines, cytokines,growth factors, enzymes, blood proteins such as hemoglobin,α-1-antitrypsin, fibrinogen, human serum albumin, prothrombin/thrombin,antibodies, blood coagulation and/or clotting factors, and biologicallyactive fragments thereof, such as Factor V, Factor VI, Factor VII,Factor VIII and derivatives thereof such as B-domain deleted FVIII,Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, FletcherFactor, Fitzgerald Factor, and von Willebrand Factor; milk proteins suchas casein, lactoferrin, lysozyme, α-1-antitrypsin, protein factors,immune proteins, and biologically active fragments thereof; andantibodies, including monoclonal antibodies, single chain antibodies,antibody fragments, chimeric antibodies, humanized antibodies, and otherantibody variant molecules which can be produced in recombinant cellculture.

The biopharmaceutical product may be derived from cell culture. The cellculture may comprise any type of cell including a plant, insect,mammalian, yeast or bacterial cell. In one embodiment, thebiopharmaceutical product is an ultrafiltered/diafiltered (UF/DF)solution obtained from cell culture. In another embodiment thebiopharmaceutical product is an ultrafiltered/tissue cultureconcentrated filtered (UF/TCF) solution obtained from cell culture.

In one embodiment, the biopharmaceutical product is recombinant FactorVIII. Factor VIII as used herein includes engineered variants of FactorVIII, such as B-domain deleted variants of Factor VIII and site-specificmutation variants of Factor VIII or of B-domain deleted Factor VIII. Thebiopharmaceutical product may be a derivative of Factor VIII havingFactor VIII procoagulant activity.

During processing, the biopharmaceutical product 8 is inserted into apolymeric product container 12. Depending upon the product used and itsprocessing specifications, after this insertion step, the product andthe product container may be frozen. Moreover, depending upon thefreezing technique used by a biopharmaceutical manufacturer, both theproduct and the product container may be subject to significant stress,as the product changes from a liquid to a frozen state. Freezingtechniques can, therefore, result in osmotic stresses and other types ofstresses due to ice interface formation, pH changes, and phaseseparation.

Many manufacturers agree that it is generally better to blast freeze orsupercool biopharmaceutical products using liquid nitrogen and water ordry ice and/or ethanol baths. In one type of blast freezing process,filled polymeric product containers are blast frozen in a freezer havinga temperature of about −56° C. Unfortunately, this type of technique maydamage polymeric product containers due to their fragility at lowertemperatures.

Once a product is frozen, some products, like proteins, must maintaintemperature stability for long periods. Biopharmaceutical products maybe maintained at temperatures as low as −10, −20, −30, −40, −50 or −100°C. After freezing, the product is often transported to another locationfor long-term storage. During the handling, transporting, and storage,the temperature of the product and the polymeric product container mustremain relatively stable, often at a temperature of −30° C. or less.Storage at this temperature may be maintained for a long term, such asfor a time period of at least 30, 60, 90, or 180 days. Often freezingoccurs at one site in the manufacturing facility and the long termstorage is at a second site some distance away. Therefore, safetransport conditions which protect fragile frozen product and productcontainers are needed.

When product is ready for further purification and formulation, it mustbe thawed. Many thawing techniques agitate products to speed up thethawing process. Agitation, however, further subjects polymeric productcontainers to additional stress, which may result in areas where productleakage can occur.

In one configuration, the polymeric product container 12 comprises abioprocess bag having a generally rectangular shape, as shown in FIGS. 1and 2A. Containers of other shapes, however, are suitable. In oneembodiment, the container 12 is manufactured from a natural or syntheticpolymeric material. This material has a thickness, as specified by theproduct manufacturer, and acceptable flexibility and compatibility withthe biopharmaceutical product 8. Further, the material is not to bereactive, additive, or absorptive such that the purity, strength, oridentity of the product is compromised. Some compatibility tests used bybiopharmaceutical product manufacturers include those performedaccording to U.S. Pharmacopeia Reference Standards.

Materials typically used for product container such as bioprocess bagsinclude thermoplastic materials, such as copolymers of ethylene andvinyl acetate (EVA) and polyvinylidene fluoride (PVDF) and polyolefinhomopolymers, such as polyethylene and polypropylene,polytetrafluoroethylene, and silicone. Various other polymer blends,however, may be suitable. Bioprocess bags may include those manufacturedby Arkema, Inc., DuPont, Dow Chemical Company, Sartorius-Stedim BiotechS.A. and Charter Medical, Ltd., among other manufacturers.

In addition to compatibility requirements, the polymeric productcontainer should meet additional product specific validation andbiocompatibility requirements. Typically, these validation requirementsare specified by the biopharmaceutical product manufacturer and relateto sterility of the polymeric product container, product stability,product adsorption, etc. Other validation requirements may be set byother authorities. These requirements include, but are not limited to,acceptable limits for leachables, extractables, gas permeability, andcontainer integrity. Some manufacturers perform validation and/orqualification testing by inserting biopharmaceutical products intoproduct containers and then measuring affects of the container on theproduct over a specified duration.

As shown in FIG. 2B, the product container 12 may have two or morelayers, such as a contact layer 13 a and one or more backing layers 13b. These materials are coupled using any method sanctioned by thebiopharmaceutical product manufacturer. These methods may include theuse of tie layer adhesives, for example.

The contact layer 13 a comes in contact with the biopharmaceuticalproduct 8 and should thus be compatible with the biopharmaceuticalproduct. The biopharmaceutical product 8 should also not unacceptablydegrade, react, or absorb when in contact with the contact layer 13 a.The contact layer must, therefore, have a thickness that preventsunacceptable effects on the product over long periods. In someembodiments, the contact layer 13 a has a thickness of about 360 μm.

The contact layer 13 a may also be specified to meet validationrequirements, as specified by the biopharmaceutical productmanufacturer. These requirements may include specified parameters forgas permeability, sterilization, chemical compatibility, leachables, andextractables. Suitable materials for the contact layer include, but arenot limited to, ethylene vinyl acetate (EVA), ethyl vinyl alcohol(EVOH), polyethylene, polyvinylidene fluoride, polytetrafluoroethylene,and polypropylene (low density and high density).

In some product containers, one or more backing layers 13 b areconfigured to provide dimensional stability and structural support. Thebacking layer 13 b may be manufactured from various types of polymericmaterials. These materials may include EVA, polyolefins, nylon, andpolyesters.

In assessing the validation requirements for the contact layer 13 a,certain material properties may be specified. For example, in someembodiments the contact layer 13 a may have a density of about 0.94g/cm³. Additional material properties of the contact layer 13 a mayinclude tensile strength at 100% elongation of about 6 MPa (870 psi) andan elastic modulus of about 50 MPa (7.25 kpsi). These properties may bemeasured, using accepted industry standards, including but not limitedto ISO 527-2.

As shown in FIG. 2A, the product container 12 has at least one opening18 for receiving and transferring the biopharmaceutical product 8. Theopening 18 has any suitable reclosable sealing element 19 that allowsfor insertion and later removal of the biopharmaceutical product 8.

After the product container 12 is filled and frozen, it is placed into aprotective envelope 14 that protects the product container 12 and allowsthe biopharmaceutical product to maintain its temperature duringtransport and handling. The product container 12 comprises mineralfibers 28 (FIG. 4) that protect and insulate the container 12 and theproduct 8, as further described below. The use of the protectiveenvelope 14, therefore, shields the product 8 and the product container12 from physical damage during handling, transport, and storage, such asphysical damage from jostling during transport to storage areas and fromaccidental dropping of the product container during such transport orstorage. As such, the biopharmaceutical product storage system protectsthe product from leakage as it undergoes the conditions offreeze-storage-thaw cycles. Generally, these cycles have a broadtemperature range of −100° C. to 8° C., inclusive. In other cases, thefreeze-storage-thaw cycle ranges from −30° C. to 2° C., inclusive.

In one embodiment, the protective envelope 14 comprises one or moreinsulation sections 20, as shown particularly in FIG. 4. An insulationsection 20 comprises at least three layers: a first layer 22, at leastone protective and insulative layer 24, and at least one second layer26. The first layer 22 and the second layer 26 may be made from aresilient material that is resistant to tears, cracks, and punctures.Depending on the overall thickness of the material, its shear strengthranges from about 124 MPa (18 kpsi) to about 150 MPa (22 kpsi). Thematerial typically maintains dimensional stability over a widetemperature range from about −70° C. to about 150° C. and, under certainconditions, is suitable for use at temperatures from about −250° C. toabout 200° C.

In one embodiment, the first layer 22 should also be compatible with theproduct container, while the second layer 26 should be suitable fordirect contact during handling by manufacturing personnel. The first andsecond layers 22, 26 are made from the same material. In oneconfiguration, these layers are made from a polyester based materialsuch as biaxially-oriented polyethylene terphthalate (“BoPet”). Onecommercially available type of BoPet is Mylar®, manufactured by DuPontTeijin Films. Biodegradable plastics are also suitable materials.

As shown in FIG. 4, disposed between the first and second layers 22, 26is a protective and insulative layer 24. The layer 24, therefore,provides insulation to maintain the temperature of a frozen or chilledbiopharmaceutical product, as specified by the product manufacturer. Thelayer 24 also is protective in that it surrounds the protective envelope14 and the product container 12 during handling, thereby providingimpact resistance. Impact resistance, as used herein, is the ability ofmaterials to withstand applied forces without damage, where damage ispunctures, tears, or other disruptions in the product container thatcauses leakage of the biopharmaceutical product 8.

This protective and insulative layer 24 may also be eco-friendly,biodegradable, and generally semi-rigid. In one embodiment, the layer 24comprises one or more mineral fibers 28 made from rock and/or slag. Insome embodiments, the rock material is basalt rock. Basalt rock is avolcanic rock generally comprising plagioclase, pyroxene, and olivine.Before formation into a mineral fiber, basalt rock is hard and densewith a glassy appearance. After the rock is formed into a fiber, itsdensity ranges from about 2.7 g/cm³ to about 2.9 g/cm³. Slag materialsare byproducts of various types of metallurgical operations. Thesematerials are generally non-metallic and comprise oxides of silica,lime, alumina and magnesia. After the slag is cooled and solidified, itmay be spun to form mineral fibers. Where the fibers are manufacturedfrom a combination or basalt rock and recycled slag, the rock and slagare heated to approximately 1540° C. (2000° F.), until in a moltenstate. After the molt is cooled and solidified, it is spun to formmineral fibers 28. The fibers 28 are used to form the protective andinsulative layer 24.

The first layer 22 and the second layer 26 are each cut into a similarshape. The shape of these layers is shown as substantially rectangular;however, any shape may be used to form the insulating section 20. Asshown in FIGS. 4-5, the protective and insulative layer 24 is placed inbetween the first layer 22 and the second layer 26 in one or moreinsulating areas 32 such that there are layer sealing areas 34 aroundthe peripheries of the first and second layers 22, 26. Optionally,either or both of the first and second layers may extend beyond the areaof the protective and insulative layer 24 to form a flap 30. In anotheroptional configuration, the mineral fiber is placed on two or moreseparate insulating areas (not shown) between the first and secondlayer.

In one embodiment, the layers 22, 26 are sealed with an adhesive suchthat the mineral fiber is encompassed within the layers. The adhesiveused should be suitable for temperatures as low as −100° C. such thatthe seal is maintained. After sealing of the protective and protectiveand insulative layer 24, an insulation section 20 is formed. One exampleof an insulation section 20 is CONTROL TEMP PACKAGING® material,manufactured by R.N.C. Industries Inc., Norcross, Ga. The overallthickness of the insulation section 20 depends on the temperaturespecifications set by the product manufacturer. In one configuration,the insulation section 20 has an approximate overall thickness of about1 inch. One or more insulation sections 20 may be used to form theprotective envelope 14.

As shown in FIG. 5, a pre-assembled protective envelope 14′ has a widththat is about one-half of the approximate length. In anotherconfiguration, the envelope 14′ has a width of about 21 inches and alength of about 59 inches and contains a 5-liter product container.These dimensions, however, are not to be construed as limiting, butshould be determined, in part, by the size of the product container 12housed within the envelope. Located on the pre-assembled protectiveenvelope 14 are envelope sealing sections 44, which are used with anadhesive or a mechanical sealing method, e.g. VELCRO™ hook and loopfasteners, to form the envelope. Where an adhesive is used, it issuitable for temperatures as low as −100° C. such that a seal ismaintained. Before the protective envelope is formed, it can be foldedto form a fold line 46.

FIGS. 6 and 7 show the protective envelope 14 after assembly. Whenassembled or formed, the protective envelope 14 is adapted to have afront wall 60, a back wall 62, a base 64, and a top 66. In oneconfiguration, the front wall 60, back wall 62, and base 64 are madefrom three insulation sections 20. The top 66 is made from a plasticmaterial and attached to a back edge 68 of the envelope using anadhesive. Other methods of attachment may, however, be suitable.Optionally, the top 66 is made using the flap 30. Alternatively, theflap is made from another material and separately attached to the backedge 68 of the back wall 62. The flap 30 is adapted to extend from thetop 66 and positioned to extend from the back edge 68 to an area on thefront wall 60.

Optionally, the protective envelope 14 may have a pouch 48 for insertionof a label 56. The pouch 48 is made from a transparent plastic materialand adhesively or mechanically attached to the flap 30. The label 56 isinserted into the pouch 48 to allow for product identification, usingbar code labeling or other acceptable methods of identification. In oneconfiguration, the pouch is a 6 in.×4 in. piece of transparent plasticadhesively attached to an area on the outside of the flap. The pouchmay, however, be any desired size and placed on any other area on theenvelope for identification purposes.

Additionally, the protective envelope 14 may include an envelope closureelement 50. This element provides for secure closure of the envelopeduring handling, transport, and storage. The envelope closure element 50is reclosable and made using VELCRO™ hook and loop fasteners strips.These strips are then attached to a closure area 52 located on theoutside of the protective envelope and an inside edge 54 of the flap.

Optionally, the system 10 can also include at least one cushioning layer16 disposed between the product container 12 and the protective envelope14. This cushioning layer 16 allows for additional insulation andproduct protection. As shown in FIGS. 4 and 5, the cushioning layer 16is made from the same materials and has the same general configurationas the insulation section 20. In one embodiment, the cushioning layercomprises at least one first layer 72, at least one protective andinsulative layer 74, and at least one second layer 76, where the layer74 includes mineral fibers 78. Other types of cushioning materials maybe suitable, depending upon the application and the expected level ofproduct handling. Another suitable material for the cushioning layer 16is one or more layers of expanded polystyrene foam.

By combining the product container 12, the protective envelope 14, andoptionally the cushioning layer 16, the system substantially preventsdamage to the product container 12 that would result in exposure of thebiopharmaceutical product 8 during product handling, storage, andtransport, and substantially prevents liquid leakage of the product whena frozen biopharmaceutical product is subsequently thawed for furtherprocessing. The biopharmaceutical product storage systems 10, therefore,protect and insulate the product 8 during the conditions of thefreeze-storage-thaw cycle and substantially prevent leakage uponthawing, which may result if the product container has been damagedduring the cycle. This substantial leakage prevention can be measuredwhen, for example, at least 100 product containers are subjected to afreeze-storage-thaw cycle and fewer than 10, 9, 8, 7, 6, 5, 4, 3, 2 or1% of the product containers leak during the cycle or upon thawing. Thismeasurement may be made under any standard conditions offreeze-storage-thaw cycles known to one of skill in the art for thebiopharmaceutical product, and may be, for example, freezingtemperatures of −30° C. and storage of at least 30, 60, 90, or 180 daysand thawing to a temperature of between 2° C. and 8° C.

The biopharmaceutical product storage system for use with abiopharmaceutical product subjected to a freeze-storage-thaw cycle cancomprise:

-   -   a polymeric product container configured to house the        biopharmaceutical product at a temperature ranging from −100° C.        to 8° C.; and    -   a protective envelope configured to house the polymeric product        container, the protective envelope comprising at least one        insulation section including a first layer, a second layer, and        a protective and insulative layer disposed between the first        layer and the second layer, wherein the first layer and the        second layer are sealed to contain the protective and insulative        layer, wherein the system substantially prevents leakage of the        biopharmaceutical product subjected to the freeze-storage-thaw        cycle.        The polymeric product container can comprises a bioprocess bag,        where the bioprocess bag comprises ethylene vinyl acetate or        polypropylene. Further, the polymeric product container can        comprise a contact layer and at least one backing layer, where        the contact layer and/or the backing layer comprise ethylene        vinyl acetate. Moreover, the biopharmaceutical product storage        system may further comprise a flap adapted to extend from a back        edge of the protective envelope to a front wall of the        protective envelope, a pouch positioned on the protective        envelope, and a cushioning layer disposed within the protective        envelope that is comprised of mineral fibers.

While various embodiments have been shown and described, it will beapparent to those skilled in the art that many more modifications arepossible without departing from the inventive concepts herein.

1. A protective envelope for a biopharmaceutical product subjected to afreeze-storage-thaw cycle, comprising: a product container filled withthe biopharmaceutical product; and at least one insulation section,comprising: a first layer, a second layer, and a protective andinsulative layer having mineral fibers that insulate the product andprotect the filled product container.
 2. The protective envelope ofclaim 1, wherein the mineral fibers have a density ranging from about2.7 g/cm³ to about 2.9 g/cm³.
 3. The protective envelope of claim 1,wherein the mineral fibers comprise basalt rock.
 4. The protectiveenvelope of claim 1, where the mineral fibers comprise plagioclase. 5.The protective envelope of claim 1, wherein the mineral fibers comprisepyroxene.
 6. The protective envelope of claim 1, wherein the mineralfibers comprise olivine.
 7. The protective envelope of claim 1, whereinthe mineral fibers comprise slag.
 8. The protective envelope of claim 1,wherein the mineral fibers comprise basalt rock and slag.
 9. Theprotective envelope of claim 1, wherein the first layer comprises apolymeric material.
 10. The protective envelope of claim 1, wherein thesecond layer comprises a polymeric material.
 11. The protective envelopeof claim 1, wherein the first layer comprises biaxially-orientedpolyethylene terphthalate.
 12. The protective envelope of claim 1,wherein the second layer comprises biaxially-oriented polyethyleneterphthalate.
 13. The protective envelope of claim 1, wherein the firstlayer has shear strength from about 18 kpsi to about 22 kpsi.
 14. Thebiopharmaceutical product storage system of claim 1, wherein the secondlayer has shear strength from about 18 kpsi to about 22 kpsi.
 15. Amethod of protecting a biopharmaceutical product subjected to afreeze-storage-thaw cycle comprising: (a) inserting thebiopharmaceutical product into a polymeric product container, whereinthe polymeric product container is configured to house thebiopharmaceutical product at a temperature ranging from −100° C. to 8°C.; (b) subjecting the biopharmaceutical product and the polymericproduct container to a temperature that freezes the biopharmaceuticalproduct; and (c) inserting the polymeric product container, having thefrozen biopharmaceutical product, into a protective envelope, theprotective envelope comprising at least one insulation section includinga first layer, a second layer, and an protective and insulative layerdisposed between the first layer and the second layer, wherein the firstlayer and the second layer are sealed to contain the protective andinsulative layer, and wherein the protective envelope and the polymericproduct container form a system that substantially prevents leakage ofthe biopharmaceutical product during the freeze-storage-thaw cycle. 16.A kit comprising: a polymeric product container configured to house abiopharmaceutical product at a temperature ranging from −100° C. to 8°C.; and a protective envelope comprising at least one insulation sectionincluding a first layer, a second layer, and a protective and insulativelayer disposed between the first layer and the second layer, wherein theprotective and insulative layer comprises mineral fibers and first layerand the second layer are sealed to contain the protective and insulativelayer.